U.S. patent number 7,144,422 [Application Number 10/293,108] was granted by the patent office on 2006-12-05 for drug-eluting stent and methods of making the same.
This patent grant is currently assigned to Advanced Cardiovascular Systems, Inc.. Invention is credited to K. T. Venkateswara Rao.
United States Patent |
7,144,422 |
Rao |
December 5, 2006 |
Drug-eluting stent and methods of making the same
Abstract
An intravascular stent having a prefabricated, patterned
polymeric sleeve for controlled release of therapeutic drugs and
for delivery of the therapeutic drugs in localized drug therapy in
a blood vessel is disclosed. The polymeric sleeve is attached to at
least a portion of an outside surface area of the stent structure.
Alternatively, a plurality of individual microfilament strands are
longitudinally attached to an outer surface of a stent structure in
a spaced apart orientation and loaded with at least one therapeutic
drug for the release thereof at a treatment site. The stent has a
high degree of flexibility in the longitudinal direction, yet has
adequate vessel wall coverage and radial strength sufficient to
hold open an artery or other body lumen. Methods for making the
same are also disclosed.
Inventors: |
Rao; K. T. Venkateswara (San
Jose, CA) |
Assignee: |
Advanced Cardiovascular Systems,
Inc. (Santa Clara, CA)
|
Family
ID: |
37480581 |
Appl.
No.: |
10/293,108 |
Filed: |
November 13, 2002 |
Current U.S.
Class: |
623/1.42;
623/1.15; 623/1.13 |
Current CPC
Class: |
A61F
2/91 (20130101); A61F 2/915 (20130101); A61L
31/10 (20130101); A61L 31/16 (20130101); A61F
2002/91508 (20130101); A61F 2002/91533 (20130101); A61F
2002/91575 (20130101); A61F 2250/0068 (20130101); A61F
2250/0071 (20130101); A61F 2230/0054 (20130101) |
Current International
Class: |
A61F
2/06 (20060101) |
Field of
Search: |
;623/1.15,1.13,1.12,1.23,1.39,1.42,1.44 |
References Cited
[Referenced By]
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|
Primary Examiner: Snow; Bruce
Attorney, Agent or Firm: Squire, Sanders & Dempsey
L.L.P.
Claims
What is claimed is:
1. A drug-eluting stent delivery system for controlled release of
therapeutic drugs and for delivery of the therapeutic drugs in
localized drug therapy in a blood vessel, comprising: a pattern of
struts interconnected to form a structure capable of contacting the
walls of a body lumen to maintain the patency of the vessel,
wherein a polymeric sleeve, fabricated as a prepatterned tube
comprising polymer elements, is loaded with at least one
therapeutic drug for the release thereof at a treatment site, the
polymeric sleeve being attached to at least a portion of an outside
surface area of the stent structure and wherein the prepatterning
enables the detachment of the polymer elements upon stent
expansion, wherein the polymeric sleeve includes a plurality of
four-sided, filament strands attached to the surface of the stent,
and wherein a barrier coating layer is disposed on three sides of
the plurality of four-sided filament strands to enable drug elution
along the fourth side.
2. The drug-eluting stent delivery system of claim 1, wherein the
pattern of struts comprises a plurality of flexible cylindrical
rings being expandable in a radial direction, each of the rings
having a first delivery diameter and a second implanted diameter
and being aligned on a common longitudinal axis.
3. The drug-eluting stent delivery system of claim 1, wherein the
stent is formed at least in part of a metallic material.
4. The drug-eluting stent delivery system of claim 3, wherein the
metallic material forming the stent is from the group consisting of
stainless steel, platinum, titanium, tantalum, nickel-titanium,
cobalt-chromium, and alloys thereof.
5. The drug-eluting stent delivery system of claim 1, wherein the
therapeutic drug is selected from the group consisting of
antiplatelets, anticoagulants, antifibrins, antithrombins, and
antiproliferatives.
6. The drug-eluting stent delivery system of claim 1, wherein the
polymeric sleeve comprises a material selected from the group
consisting of PMMA, EVAL, PBMA, PGA, and PLLA, and copolymers and
blends thereof.
7. The drug-eluting stent delivery system of claim 1, wherein the
polymeric sleeve is fabricated from a predesigned pattern having
individual drug-loaded elements to form a desired local
drug-elution profile.
8. The drug-eluting stent delivery system of claim 7, wherein upon
expansion of the stent structure, the drug-loaded polymeric sleeve
breaks away in the predesigned pattern and individual drug-loaded
filament strands are held against the vessel wall by the stent
structure.
9. The drug-eluting stent delivery system of claim 7, wherein the
predesigned pattern is fabricated to expand along a length of the
stent to overcome strain.
10. The drug-eluting stent delivery system of claim 1, wherein the
drug-loaded polymeric sleeve is prefabricated in a desired
dimension using at least one of the polymer processing techniques
comprising extrusion, injection molding, laser cutting, slip
casting, and plasma polymerization.
11. The drug-eluting stent delivery system of claim 1, wherein the
polymeric sleeve includes at least one additional layer of polymer
material as a barrier layer to further control elution of the
therapeutic drug at the treatment site.
12. The drug-eluting stent delivery system of claim 1, wherein the
drug-loaded polymeric sleeve has a thickness in the range of about
0.001 to about 100 microns.
13. A method of making a drug-eluting stent delivery system for
controlled release of therapeutic drug(s) and for delivery of the
therapeutic drug(s) in localized drug therapy in a blood vessel,
comprising: forming a pattern of struts that form a stent capable
of contacting the walls of a body lumen to maintain the patency of
the vessel, wherein at least a portion of the outside surface of
the stent surface attaches to a polymeric sleeve that is fabricated
as a prepatterned tube comprising a plurality of four-sided,
filament strands attached to the surface of the stent, and is
loaded with at least one therapeutic drug for the release thereof
at a treatment site, wherein the prepatterning enables the
detachment of the filament strands upon stent expansion, and
wherein a barrier coating layer is disposed on three sides of the
plurality of four-sided filament strands to enable drug elution
along the fourth side.
14. The method of claim 13 wherein the therapeutic drug is selected
from the group consisting of antiplatelets, anticoagulants,
antifibrins, antithrombins, and antiproliferatives.
15. The method of claim 13 wherein the polymeric sleeve comprises a
material selected from PMMA, EVAL, PBMA, PGA, PLLA, copolymers
thereof or blends thereof.
16. The method of claim 13 wherein the polymeric sleeve includes at
least one additional layer of polymer material as a barrier layer
to further control elution of the therapeutic drug at the treatment
site.
Description
BACKGROUND OF THE INVENTION
This invention relates to vascular repair devices, and in
particular intravascular stents, which are adapted to be implanted
into a patient's body lumen, such as a blood vessel or coronary
artery, to maintain the patency thereof. Stents are particularly
useful in the treatment of atherosclerotic stenosis in arteries and
blood vessels. More particularly, the invention concerns a
drug-eluting stent delivery system consisting of an intravascular
device having a local drug-eluting component that is capable of
eluting therapeutic drugs with uniform and controlled drug
distribution at the treatment site while providing the
intravascular device with a biocompatible and/or hemocompatible
surface.
Intravascular interventional devices such as stents are typically
implanted within a vessel in a contracted state, and expanded when
in place in the vessel in order to maintain the patency of the
vessel to allow fluid flow through the vessel. Stents have a
support structure such as a metallic structure to provide the
strength required to maintain the patency of the vessel in which it
is to be implanted, and are typically provided with an exterior
surface coating to provide a biocompatible and/or hemocompatible
surface. Since it is often useful to provide localized therapeutic
pharmacological treatment of a blood vessel at the location being
treated with the stent, it is also desirable to provide
intravascular interventional devices such as stents with a
biocompatible and/or hemocompatible surface coating of a polymeric
material with the capability of being loaded with therapeutic
agents, to function together with the intravascular devices for
placement and release of the therapeutic drugs at a specific
intravascular site.
Drug-eluting stent devices have shown great promise in treating
coronary artery disease, specifically in terms of reopening and
restoring blood flow in arteries stenosed by atherosclerosis.
Restenosis rates after using drug-eluting stents during
percutaneous intervention are significantly lower compared to bare
metal stenting and balloon angioplasty. However, current design and
fabrication methods for drug-eluting stent devices are not optimal.
Accordingly, various limitations exist with respect to such current
design and fabrication methods for drug-eluting stents.
One significant limitation, for example, is that current designs
for drug-eluting stents fail to provide for uniform drug
distribution in the artery. Since unformity is dictated by metal
stent skeletal structure, increasing uniformity by increasing the
metal stent surface area makes the stent stiff and compromises
flexibility and deliverability. Additionally, current device
designs incorporate expandable ring elements and connectors, which
are then coated using a polymer plus drug coating or loaded with
microreservoirs of drug. The expandable nature of the rings limits
the extent of uniformity in coverage and drug distribution that can
be achieved. Further limitations include the mixture of the drug in
a polymer and/or solvent solution which is then spray coated on the
entire stent surface with a primer, drug, and topcoat layers being
used to control release kinetics. This approach, tends to cause
cracking in the drug-coating layer, since the layer also undergoes
stretching during stent expansion, and considerable washout of the
drug into the blood stream, and only a fraction gets into the
tissue/artery. Further, the amount of the drug that can be loaded
on the stent is limited by mechanical properties of the coating,
since the higher the drug content in the polymer makes the coating
more brittle and causes cracking thereto. Therefore, loading a
higher drug dose requires coating with more polymer on the device.
Other limitations in current fabrication methods of drug-eluting
stents include the necessity of several coating steps along the
length of the stent which is time consuming. Special equipment for
crimping the drug-eluting stent on the balloon and to securely
attach the stent on the balloon is also needed in accordance with
current fabrication methods. As conventional spray coating is
capable of programming only one drug release rate kinetics,
variation of drug dosing and release kinetics along the length of
the stent is not possible using the current coating process.
What has been needed and heretofore unavailable is a novel design
that decouples the two major functional characteristics of the
drug-eluting stent device, namely the purely mechanical stent
structure and the local drug-eluting component. Current devices are
constrained by their design construct which necessitates optimizing
both factors-mechanical stent expansion and drug-elution kinetics
simultaneously. Thus, it would be desirable to have a stent
structure that is optimally designed for expansion (i.e., allowable
stress/strain, scaffolding, radial strength, etc.) independent of
the drug-eluting component, and the drug-eluting component designed
for local drug release independent of mechanical factors associated
with stent expansion. The present invention meets these and other
needs.
SUMMARY OF THE INVENTION
The present invention is directed to intraluminal devices, and more
particularly, to a drug-eluting stent delivery system for
controlled release of therapeutic drugs and for delivery of the
therapeutic drugs in localized drug therapy in a blood vessel.
Alternatively, the drug-eluting stent delivery system includes a
plurality of individual filament strands attached in a spaced apart
orientation around an outside surface area of the stent and loaded
with at least one therapeutic drug for the controlled release
thereof at a treatment site. Methods for making different types of
a drug-eluting stent delivery system are also disclosed herein.
In one embodiment, the present invention accordingly provides for a
drug-eluting stent delivery system for controlled release of
therapeutic drugs and for delivery of the therapeutic drugs in
localized drug therapy in a blood vessel. A pattern of struts are
interconnected to form a structure that contacts the walls of a
body lumen to maintain the patency of the vessel. The pattern of
struts include a plurality of flexible cylindrical rings being
expandable in a radial direction with each of the rings having a
first delivery diameter and a second implanted diameter while
aligned on a common longitudinal axis. At least one link of the
stent is attached between adjacent rings to form the stent. The
stent is formed at least in part of a metallic material such as
stainless steel, platinum, titanium, tantalum, nickel-titanium,
cobalt-chromium or alloys thereof.
A polymeric sleeve, fabricated as a prepatterned tube, is loaded
with at least one therapeutic drug for the release thereof at a
treatment site. The polymeric sleeve is attached to at least a
portion of an outside surface area of the stent structure. Various
therapeutic drugs that can be used in combination with the
polymeric sleeve include antiplatelets, anticoagulants,
antifibrins, antiinflammatories, antithrombins, and
antiproliferatives. Several drug-loadable polymers, such as PMMA,
EVAL, PBMA, PGA, PLLA, copolymers and blends thereof, and nanotubes
of carbon can be used to fabricate the drug-loaded sleeve of the
invention. The thickness of the drug-loaded polymeric sleeve ranges
from about 0.001 to about 100 microns.
The polymeric sleeve is fabricated from a predesigned pattern
having individual drug-loaded elements to form a desired local
drug-elution profile. The predesigned pattern of the polymeric
sleeve as a solid tube can be formed by various techniques such as
etching or cutting. The drug-loaded polymeric sleeve is
prefabricated in a desired dimension by using one of the known
polymer processing techniques in the art including extrusion,
injection molding, laser cutting, slip casting, and plasma
polymerization. As a further mechanism of controlling elution of
the therapeutic drug at the treatment site, the polymeric sleeve
can be coated with at least one additional layer of polymer
material as a barrier layer.
In use, the drug-loaded polymeric sleeve breaks away in the
predesigned pattern upon expansion of the underlying stent
structure and individual drug-loaded elements are held against the
vessel wall by the stent structure. The predesigned pattern is
fabricated to expand along a length of the stent to overcome
strain.
In another embodiment, the present invention provides for a
drug-eluting stent delivery system for controlled release of
therapeutic drugs and for delivery of the therapeutic drugs in
localized drug therapy in a blood vessel. A pattern of struts are
interconnected to form a first stent structure that contacts the
walls of a body lumen to maintain the patency of the vessel,
wherein a second stent structure, fabricated as a prepatterned thin
metallic sheet having a polymer layer disposed thereon, is loaded
with at least one therapeutic drug for the release thereof at a
treatment site. The second stent structure is attached to at least
a portion of an outside surface area of the stent structure. The
second stent structure is not limited to a tubular form and can be
wrapped around the first stent structure in a jelly roll
configuration.
In a further embodiment, the present invention provides for a
drug-eluting stent delivery system for controlled release of
therapeutic drugs and for delivery of the therapeutic drugs in
localized drug therapy in a blood vessel. A pattern of struts are
interconnected to form a structure that contacts the walls of the
body lumen to maintain the patency of the vessel. A plurality of
individual filament strands are attached to an outside surface of
the stent structure in a spaced apart orientation and loaded with
at least one therapeutic drug for the release thereof at a
treatment site. The plurality of individual filament strands are
positioned longitudinally across the outside surface of the stent
structure.
The pattern of struts include a plurality of flexible cylindrical
rings being expandable in a radial direction, each of the rings
having a first delivery diameter and a second implanted diameter
while aligned on a common longitudinal axis. At least one link of
the stent is attached between adjacent rings to form the stent. The
stent is formed at least in part of a metallic material such as
stainless steel, platinum, titanium, tantalum, nickel-titanium,
cobalt-chromium, and alloys thereof.
Various therapeutic drugs can be used in combination with the
drug-eluting stent delivery system of the present invention
including antiplatelets, anticoagulants, antifibrins,
antiinflammatories, antithrombins, and antiproliferatives. The
plurality of individual filament strands can be fabricated using
different therapeutic drug combinations for the release thereof at
the treatment site. The drug-loaded filament strands each have a
thickness in the range of about 0.001 to about 100 microns and a
width in the range of about 0.001 to about 50 microns. Several
drug-loadable polymers, such as PMMA, EVAL, PBMA, PGA, PLLA,
copolymers and blends thereof, and nanotubes of carbon can be used
to fabricate the individual filament strands. Alternatively, the
plurality of individual filament strands are fabricated from a
porous metal having a polymeric drug release layer disposed
thereon.
Each of the individual filament strands have a rectangular
cross-section with a first side, a second side, a third side, and a
fourth side. A barrier coating layer is disposed on the first,
second, and third sides of each of the drug-loaded filament strands
to enable drug elution along the fourth side at the treatment site.
Alternatively, the plurality of individual filament strands can be
configured to assume a different cross-sectional design such as
circular, oval, triangular, trapezoidal, and tubular designs. The
individual filament strands can be fabricated from either a
micron-scale level or a nano-scale level to form microfilament
strands or nanofilament strands, respectively.
In another embodiment, the present invention provides for a
drug-eluting stent delivery system for controlled release of
therapeutic drugs and for delivery of the therapeutic drugs in
localized drug therapy in a blood vessel. A pattern of struts are
interconnected to form a structure that contacts the walls of a
body lumen to maintain the patency of the vessel. A polymeric
sleeve, fabricated as a prepatterned tube, is loaded with at least
one therapeutic drug for the release thereof at a treatment site,
the polymeric sleeve being attached to at least a portion of an
inside surface area of the stent structure for the treatment of the
inner arterial region of the vessel.
In yet another embodiment, the present invention provides for a
method of making a drug-eluting stent delivery system for
controlled release of therapeutic drugs and for delivery of the
therapeutic drugs in localized drug therapy in a blood vessel. The
method includes providing a pattern of struts interconnected to
form a structure that contacts the walls of a body lumen to
maintain the patency of the vessel. A polymeric sleeve, fabricated
as a prepatterned tube, is attached to at least a portion of an
outside surface area of the stent structure. The polymeric sleeve
is loaded with at least one therapeutic drug for the release
thereof at a treatment site.
In a further embodiment, the present invention provides for a
method of making a drug-eluting stent delivery system for
controlled release of therapeutic drugs and for delivery of the
therapeutic drugs in localized drug therapy in a blood vessel. The
method includes providing a pattern of struts interconnected to
form a structure that contacts the walls of the body lumen to
maintain the patency of the vessel. A plurality of individual
filament strands are positioned longitudinally across an outside
surface of the stent structure in a spaced apart orientation and
attached thereto. The plurality of individual filament strands are
loaded with at least one therapeutic drug for the release thereof
at a treatment site.
Other features and advantages of the invention will become apparent
from the following detailed description, taken in conjunction with
the accompanying drawings, which illustrate, by way of example, the
features of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an elevational view, partially in section, of a stent
embodying features of the invention which is mounted on a delivery
catheter and disposed within a damaged artery.
FIG. 2 is an elevational view, partially in section, similar to
that shown in FIG. 1 wherein the stent is expanded within a damaged
artery.
FIG. 3 is an elevational view, partially in section, depicting the
expanded stent within the artery after withdrawal of the delivery
catheter.
FIG. 4A is a plan view of a flattened stent of the invention which
illustrates the pattern of the stent shown in FIGS. 1 3 in an
unexpanded condition.
FIG. 4B is a plan view of a flattened drug-eluting component of the
drug-eluting stent delivery system in accordance with the invention
shown in the unexpanded condition.
FIG. 4C is a plan view of the drug-eluting stent delivery system in
accordance with the invention shown in the unexpanded
condition.
FIG. 5A is a transverse, cross-sectional view of the drug-eluting
stent delivery system shown in FIG. 4A in the unexpanded
condition.
FIG. 5B is a transverse, cross-sectional view of the drug-eluting
component of the drug-eluting stent delivery system shown in FIG.
4B in the unexpanded condition.
FIG. 5C is a transverse, cross-sectional view of the drug-eluting
stent delivery system shown in FIG. 4C in the unexpanded
condition.
FIG. 6A is a plan view of the drug-eluting stent delivery system in
accordance with the invention shown in the expanded condition.
FIG. 6B is a transverse, cross-sectional view of the drug-eluting
stent delivery system of FIG. 6A shown in the expanded
condition.
FIG. 7A is a plan view of an alternative embodiment of the
invention in an expanded condition depicting a plurality of
individual filament strands for holding the therapeutic drug prior
to being released.
FIG. 7B is a transverse, cross-sectional view of the alternative
embodiment depicting a stent with the plurality of individual
filament strands attached thereto in the expanded condition.
FIG. 7C is an enlarged, transverse, cross-sectional view of a
section shown in FIG. 7B in the expanded condition.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As shown in the drawings for purposes of illustration, the present
invention is directed to a drug-eluting stent delivery system which
includes a mechanical component and a local drug-eluting component,
namely an intravascular stent and a prepatterned polymeric sleeve
for controlled release of therapeutic drugs and for delivery of the
therapeutic drugs in localized drug therapy in a blood vessel. The
present invention is also directed to an intravascular stent having
a drug-eluting component in the form of a plurality of
microfilament strands attached to an outside surface of the stent
structure in a spaced apart orientation. Methods of making a
drug-eluting stent delivery system having a drug-eluting component
disposed in the form of a prepatterned polymeric sleeve or a
plurality of microfilament strands for controlled release and
delivery of therapeutic drugs in localized drug therapy in a blood
vessel are also disclosed herein.
Turning to the drawings, FIG. 1 depicts a metallic stent 10,
incorporating features of the invention, mounted on a catheter
assembly 12 which is used to deliver the stent and implant it in a
body lumen, such as a coronary artery, carotid artery, peripheral
artery, or other vessel or lumen within the body. The stent
generally comprises a plurality of radially expandable cylindrical
rings 11 disposed generally coaxially and interconnected by
undulating links 15 disposed between adjacent cylindrical elements.
The catheter assembly includes a catheter shaft 13 which has a
proximal end 14 and a distal end 16. The catheter assembly is
configured to advance through the patient's vascular system by
advancing over a guide wire by any of the well known methods of an
over the wire system (not shown) or a well known rapid exchange
catheter system, such as the one shown in FIG. 1.
Catheter assembly 12 as depicted in FIG. 1 is of the well known
rapid exchange type which includes an RX port 20 where the guide
wire 18 will exit the catheter. The distal end of the guide wire 18
exits the catheter distal end 16 so that the catheter advances
along the guide wire on a section of the catheter between the RX
port 20 and the catheter distal end 16. As is known in the art, the
guide wire lumen which receives the guide wire is sized for
receiving various diameter guide wires to suit a particular
application. The stent is mounted on the expandable member 22
(balloon) and is crimped tightly thereon so that the stent and
expandable member present a low profile diameter for delivery
through the arteries.
As shown in FIG. 1, a partial cross-section of an artery 24 is
shown with a small amount of plaque that has been previously
treated by an angioplasty or other repair procedure. Stent 10 of
the present invention is used to repair a diseased or damaged
arterial wall which may include the plaque 25 as shown in FIG. 1,
or a dissection, or a flap which are commonly found in the coronary
arteries, carotid arteries, peripheral arteries and other
vessels.
In a typical procedure to implant stent 10, the guide wire 18 is
advanced through the patient's vascular system by well known
methods so that the distal end of the guide wire is advanced past
the plaque or diseased area 25. Prior to implanting the stent, the
cardiologist may wish to perform an angioplasty procedure or other
procedure (i.e., atherectomy) in order to open the vessel and
remodel the diseased area. Thereafter, the stent delivery catheter
assembly 12 is advanced over the guide wire so that the stent is
positioned in the target area. The expandable member or balloon 22
is inflated by well known means so that it expands radially
outwardly and in turn expands the stent radially outwardly until
the stent is apposed to the vessel wall. The expandable member is
then deflated and the catheter withdrawn from the patient's
vascular system. The guide wire typically is left in the lumen for
post-dilatation procedures, if any, and subsequently is withdrawn
from the patient's vascular system. As depicted in FIGS. 2 and 3,
the balloon is fully inflated with the stent expanded and pressed
against the vessel wall, and in FIG. 3, the implanted stent remains
in the vessel after the balloon has been deflated and the catheter
assembly and guide wire have been withdrawn from the patient.
The stent 10 serves to hold open the artery 24 after the catheter
is withdrawn, as illustrated by FIG. 3. Due to the formation of the
stent from an elongated tubular member, the undulating components
of the stent are relatively flat in transverse cross-section, so
that when the stent is expanded, it is pressed into the wall of the
artery and as a result does not interfere with the blood flow
through the artery. The stent is pressed into the wall of the
artery and will eventually be covered with endothelial cell growth
which further minimizes blood flow interference. The undulating
portion of the stent provides good tacking characteristics to
prevent stent movement within the artery. Furthermore, the closely
spaced cylindrical elements at regular intervals provide uniform
support for the wall of the artery, and consequently are well
adapted to tack up and hold in place small flaps or dissections in
the wall of the artery, as illustrated in FIGS. 2 and 3.
The stent patterns shown in FIGS. 1 3 are for illustration purposes
only and can vary in size and shape to accommodate different
vessels or body lumens. Further, the metallic stent 10 is of a type
that can be used in accordance with the present invention.
The drug-eluting stent delivery system of the present invention is
applicable to all vascular stent applications in the body including
coronary and peripheral arterial system. Further, the present
invention can be used in the treatment of vulnerable plaque such as
thin fibrous-capped atheromatic vulnerable lesions using desired
drug and release kinetics with site specificity. In addition, the
drug-eluting component of the stent system can be incorporated on
all stent platforms for all sizes and lengths including a
bifurcated stent structure to achieve uniform drug distribution
along the entire vessel including the carina. It is also
contemplated that the drug-eluting component of the present
invention can be used for designing drug-eluting stent devices with
thinner stent struts (i.e., thickness ranging between 5-100
microns) without compromising the structural integrity of the
stent, deliverability and optimal drug elution.
The present invention overcomes all of the earlier mentioned
limitations through a novel design that decouples the two major
functional characteristics of the drug-eluting stent delivery
system, namely the purely mechanical stent structure and the local
drug-eluting component. Each component is independently designed
and optimized for its functional characteristics and the optimal
drug-eluting stent delivery system is conceived and assembled. The
stent structure is optimally designed for expansion (i.e.,
allowable stress/strain, scaffolding, and radial strength), and the
local drug-eluting component is optimally designed for controlled
release of therapeutic drugs.
As shown in one embodiment, FIG. 4A is a plan view of a flattened
stent of the drug-eluting stent delivery system which illustrates
the pattern of the stent shown in FIGS. 1 3 in an unexpanded
condition. The stent 10 is shown in a flattened condition so that
the pattern can be clearly viewed, even though the stent is never
in this form. The stent is typically formed from a tubular member,
however, it can be formed from a flat sheet such as shown in FIG.
4A and rolled into a cylindrical configuration.
FIG. 4B is a flattened, plan view of a prepatterned polymeric
sleeve 26 of the stent 10 in accordance with the invention shown in
the unexpanded condition. In this embodiment, the stent having a
polymeric sleeve for controlled release of therapeutic drugs and
for delivery of the therapeutic drugs in localized drug therapy in
a blood vessel includes a pattern of struts interconnected to form
a structure that contacts the walls of a body lumen to maintain the
patency of the vessel. The pattern of struts include a plurality of
flexible cylindrical rings 11 (FIG. 4A) being expandable in a
radial direction, each of the rings having a first delivery
diameter and a second implanted diameter and being aligned on a
common longitudinal axis 17. At least one link 15 (FIG. 4A) of the
stent is attached between adjacent rings to form the stent.
With further reference to FIG. 4B, the drug-eluting polymeric
sleeve 26 is prefabricated in the desired dimensions using
conventional polymer processing methods known in the art, including
extrusion, injection molding, slip casting or plasma polymerization
using a mixture of the polymer, solvent and drug in liquid,
semi-solid or solid form. The polymeric sleeve can be fabricated
either as a prepatterned tube or a solid tube. When the polymeric
sleeve is fabricated as a solid tube, the predesigned pattern can
be attained by the known methods in the art consisting of laser
cutting or etching using the excimer or the avia solid-state laser
without any post processing. The polymeric sleeve is fabricated
from a predesigned pattern having individual drug-loaded elements
28 to form a desired local drug-elution profile. The intent of the
predesigned pattern on the polymeric sleeve is to enable the
detachment of the drug-eluting polymer elements upon stent
expansion (FIG. 6A) without undergoing stretching during balloon
expansion of the stent 10 and achieve an optimally desired
drug-elution profile. Accordingly, upon stent expansion, the
drug-loaded polymeric sleeve breaks away in the predesigned pattern
and individual drug-loaded elements are held against the vessel
wall (not shown) by the stent structure 10. The predesigned pattern
can be fabricated so that it expands along a length of the stent if
needed to overcome strain during expansion. Depending on the
desired nature of local drug elution and drug uptake into the
artery, a variety of different patterns can be etched or cut into
the polymeric material that forms the sleeve. The sleeve is
attached to the stent using conventional metal-polymer or
polymer--polymer adhesion techniques known in the art. The
drug-loaded polymeric sleeve has a thickness in the range of about
0.001 to about 100 microns.
FIG. 4C is a plan view of the drug-eluting stent delivery system 30
which includes a stent 10 with the drug-eluting component or
polymeric sleeve 26 disposed thereon in accordance with the
invention shown in the unexpanded condition.
FIGS. 5A C depict various transverse, cross-sectional views of the
two separate components of the drug-eluting stent delivery system
30, namely the mechanical stent structure 10 and the drug-eluting
component or drug-loaded polymeric sleeve 26, and one of the
complete present invention drug-eluting stent delivery system while
in an unexpanded condition. More specifically, FIG. 5A is a
transverse, cross-sectional view of the stent in FIG. 4A shown in
the unexpanded condition. FIG. 5B is a transverse, cross-sectional
view of the drug-eluting component of the stent in FIG. 4B shown in
the unexpanded condition. FIG. 5C is a transverse, cross-sectional
view of the stent with the drug-eluting component disposed thereon
in FIG. 4C shown in the unexpanded condition.
FIG. 6A illustrates a plan view of the stent 10 with the
drug-loaded polymeric sleeve 26 disposed thereon in accordance with
the invention shown in the expanded condition. The present
invention contemplates that the drug-loaded polymeric sleeve can
have at least one additional layer of polymer material as a barrier
layer to control elution of the therapeutic drug at the treatment
site. Multiple layers of polymer material disposed on the polymeric
sleeve provide further control of the elution of the therapeutic
drug at the treatment site. It should be further recognized that
the polymeric sleeve can optionally include multiple layers of the
therapeutic drug disposed thereon. Accordingly, each of the layers
of therapeutic drug can comprise a different therapeutic drug with
varying release rates or a mixture of different therapeutic drugs.
The outermost layer has a polymeric barrier coat layer to further
control elution of the therapeutic drug. FIG. 6B illustrates a
transverse, cross-sectional view of the drug-eluting stent delivery
system 30 of FIG. 6A in the expanded condition. In this embodiment,
the complete polymeric sleeve is also coated with a top coat or
barrier layer (not shown) along the inner surface to prevent
washout of the drug and increase efficiency of drug uptake into the
artery.
In an alternative embodiment, the present invention provides for a
drug-eluting stent delivery system for controlled release of
therapeutic drugs and for delivery of the therapeutic drugs in
localized drug therapy in a blood vessel. A pattern of struts are
interconnected to form a first stent structure that contacts the
walls of a body lumen to maintain the patency of the vessel. A
second stent structure, fabricated as a prepatterned thin metallic
sheet having a polymer layer disposed thereon, is loaded with at
least one therapeutic drug for the release thereof at a treatment
site, the second stent structure being attached to at least a
portion of an outside surface area of the first stent structure. It
should be appreciated that the second stent structure is not
limited to a tubular form, and can be fabricated as a thin metallic
sheet attached to the outside surface area of the first stent
structure by being wrapped around the first stent structure in a
jelly roll configuration. Various mechanisms for attaching the
second stent structure to the outside surface area of the first
stent structure are known in the art and contemplated for use with
the present invention. Examples of such mechanisms for attachment
include metal-polymer and polymer--polymer bonding technologies,
such as by adhesives and other similar methods.
In another embodiment shown in FIGS. 7A C, the present invention
accordingly provides for a drug-eluting stent delivery system 30
having a drug-eluting component 34 for controlled release of
therapeutic drugs and for delivery of the therapeutic drugs in
localized drug therapy in a blood vessel. A pattern of struts are
interconnected to form a structure 10 that contacts the walls of
the body lumen to maintain the patency of the vessel. The pattern
of struts include a plurality of flexible cylindrical rings 11
being expandable in a radial direction, each of the rings having a
first delivery diameter and a second implanted diameter and being
aligned on a common longitudinal axis 17. At least one link 15 of
the stent is attached between adjacent rings to form the stent. A
plurality of individual filament strands 34 are attached to an
outside surface 38 of the stent structure in a spaced apart
orientation, wherein the plurality of filament strands are each
loaded with at least one therapeutic drug 42 for the release
thereof at a treatment site. The plurality of individual filament
strands are each positioned longitudinally across the outside
surface of the stent structure.
FIG. 7A illustrates a typical arrangement of the individual
filament strands 34 prior to their attachment to an outside surface
of the stent structure in a spaced apart orientation. The filament
strands are pre-loaded with at least one therapeutic drug for the
eventual release thereof at the treatment site. It should be
appreciated that the present invention contemplates the use of
several different types of therapeutic drugs and drug cocktail
combinations by incorporating different filament strands fabricated
using different therapeutic drugs and therapeutic drugs with
polymers for the eventual release thereof at the treatment site.
The drug-loaded filament strands have dimensions of about 0.001 to
about 100 microns in thickness and about 0.001 to about 50 microns
in width. These filament strands can be fabricated from the micron
to nanoscale level as wires or tubes from polymers and metals.
FIG. 7B is a transverse, cross-sectional view of the alternative
embodiment of the invention, depicting a stent 10 with the
plurality of individual filaments 34 attached thereto in the
expanded condition. The plurality of individual filaments can be
attached to the outside surface 38 of the stent by utilizing one of
the techniques known in the art including metal-polymer and
polymer--polymer bonding technologies (i.e., adhesives). The
drug-loaded filaments can be designed to expand along the length of
the stent to overcome strain as a result of expansion if
necessary.
Referring to FIG. 7C, each individual drug-loaded filament strand
34 has a rectangular cross section 44 with a first side 46, second
side 48, third side 50, and a fourth side 52. A polymeric barrier
coating layer 54 is disposed on the first through third sides of
each of the drug-loaded filament strands to enable drug elution
along the fourth side at the treatment site. This layered construct
increases the efficiency of drug transfer into the artery with
minimal washout of the therapeutic drug. Accordingly, a lesser
amount of drug 42 and less polymer are needed to deliver the
appropriate therapeutic dose of drug into the artery. The local
drug release rate at specific sites along the length and diameter
of the stent can be varied by incorporating filament strands with
different drug release rates into the drug-eluting stent delivery
system. Further, the drug-loaded filament strands can have multiple
layers of polymer to control drug elution kinetics, such as a top
coat barrier layer to control or prevent drug release. Optionally,
each filament strand can comprise multiple layers for loading with
different therapeutic drugs or a mixture of different therapeutic
drugs. The outermost layer has a polymeric barrier coat layer to
further control elution of the therapeutic drug.
Other cross sectional designs may be utilized and optimized to
achieve the desired drug elution kinetics of the present invention.
Examples of alternative cross sectional designs that may be
employed for use with the drug-eluting stent delivery system
include circular, oval, triangular, trapezoidal, and tubular
designs. The plurality of individual filament strands can be
alternatively fabricated from a porous metal having a polymeric
drug release layer disposed thereon.
It should be appreciated that the drug-loaded filament strands 34
can be used in combination with the polymeric sleeve 26 embodiment.
In such an arrangement, each individual drug-loaded filament strand
is placed longitudinally along the outside surface of the polymeric
sleeve and attached thereto by polymer--polymer bonding or other
similar methods (i.e. adhesives) known in the art. A barrier
coating layer 54 is disposed on the first through third sides of
each of the drug-loaded filament strands to enable drug elution
along the fourth side at the treatment site as shown in FIG.
7C.
Alternatively, the present invention provides for a drug-eluting
stent delivery system for controlled release of therapeutic drugs
and for delivery of the therapeutic drugs in localized drug therapy
in a blood vessel. A pattern of struts are interconnected to form a
structure that contacts the walls of a body lumen to maintain the
patency of the vessel, wherein a polymeric sleeve, fabricated as a
prepatterned tube, is loaded with at least one therapeutic drug for
the release thereof at a treatment site. The polymeric sleeve can
be attached to at least a portion of an inside surface area of the
stent structure to provide for appropriate treatment of the inner
arterial region through release of the therapeutic drug in that
region of the vessel where the stent is placed.
Examples of various metals or alloys used in forming the mechanical
stent structure of the present invention drug-eluting stent
delivery system include stainless steel, platinum, titanium,
tantalum, nickel-titanium, cobalt-chromium, and alloys thereof. The
stent can also be formed of a polymeric material such as PMMA, PGA
or PLLA. Examples of various polymers used in forming the local
drug-eluting component of the drug-eluting stent delivery system
for all of the embodiments include PMMA, EVAL, PBMA, biodegradable
polymers (i.e., PGA and PLLA), copolymers and blends thereof, and
nanotubes of carbon. As set forth above, the local drug-eluting
component may be alternatively fabricated from various metals or
alloys, including stainless steel, platinum, titanium, tantalum,
nickel-titanium, cobalt-chromium, and alloys thereof.
Examples of therapeutic drugs or pharmacologic compounds that may
be loaded into the prefabricated patterned, polymeric sleeve or
individual filament strands and delivered to the target site in the
vasculature include taxol, aspirin, prostaglandins, and the like.
Various therapeutic agents such as antithrombogenic or
antiproliferative drugs are used to further control local
thrombosis. Examples of therapeutic agents or drugs that are
suitable for use in accordance with the present invention include
sirolimus, everolimus, actinomycin D (ActD), taxol, paclitaxel, or
derivatives and analogs thereof. Examples of agents include other
antiproliferative substances as well as antineoplastic,
antiinflammatory, antiplatelet, anticoagulant, antifibrin,
antithrombin, antimitotic, antibiotic, and antioxidant substances.
Examples of antineoplastics include taxol (paclitaxel and
docetaxel). Further examples of therapeutic drugs or agents include
antiplatelets, anticoagulants, antifibrins, antiinflammatories,
antithrombins, and antiproliferatives. Examples of antiplatelets,
anticoagulants, antifibrins, and antithrombins include, but are not
limited to, sodium heparin, low molecular weight heparin, hirudin,
argatroban, forskolin, vapiprost, prostacyclin and prostacyclin
analogs, dextran, D-phe-pro-arg-chloromethylketone (synthetic
antithrombin), dipyridamole, glycoprotein IIb/IIIa platelet
membrane receptor antagonist, recombinant hirudin, thrombin
inhibitor (available from Biogen located in Cambridge, Mass.), and
7E-3B.RTM. (an antiplatelet drug from Centocor located in Malvern,
Pa.). Examples of antimitotic agents include methotrexate,
azathioprine, vincristine, vinblastine, fluorouracil, adriamycin,
and mutamycin. Examples of cytostatic or antiproliferative agents
include angiopeptin (a somatostatin analog from Ibsen located in
the United Kingdom), angiotensin converting enzyme inhibitors such
as Captopril.RTM. (available from Squibb located in New York,
N.Y.), Cilazapril.RTM. (available from Hoffman-LaRoche located in
Basel, Switzerland), or Lisinopril.RTM. (available from Merck
located in Whitehouse Station, N.J.); calcium channel blockers
(such as Nifedipine), colchicine, fibroblast growth factor (FGF)
antagonists, fish oil (omega 3-fatty acid), histamine antagonists,
Lovastatin.RTM. (an inhibitor of HMG-CoA reductase, a cholesterol
lowering drug from Merck), methotrexate, monoclonal antibodies
(such as PDGF receptors), nitroprusside, phosphodiesterase
inhibitors, prostaglandin inhibitor (available from GlaxoSmithKline
located in United Kingdom), Seramin (a PDGF antagonist), serotonin
blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a
PDGF antagonist), and nitric oxide. Other therapeutic drugs or
agents which may be appropriate include alpha-interferon,
genetically engineered epithelial cells, and dexamethasone.
While the foregoing therapeutic agents have been used to prevent or
treat restenosis, they are provided by way of example and are not
meant to be limiting, since other therapeutic drugs may be
developed which are equally applicable for use with the present
invention. The treatment of diseases using the above therapeutic
agents are known in the art. The calculation of dosages, dosage
rates and appropriate duration of treatment are previously known in
the art. Furthermore, the therapeutic drugs or agents are loaded at
desired concentration levels per methods well known in the art to
render the device ready for implantation.
In use, the stent is deployed using conventional techniques. Once
in position, the therapeutic drug gradually diffuses into adjacent
tissue at a rate dictated by the parameters associated with the
polymer coat layer. The total dosage that is delivered is of course
limited by the total amount of the therapeutic drug that had been
loaded within the polymer sleeve or within each individual strand
of the plurality of microfilaments. The therapeutic drug is
selected to treat the deployment site and/or locations downstream
thereof. For example, deployment in the carotid artery will serve
to deliver such therapeutic drug to the brain.
The present invention also provides for various methods of making a
drug-eluting stent delivery system 30 for controlled release of
therapeutic drugs and for delivery of the therapeutic drugs in
localized drug therapy in a blood vessel. In one embodiment, the
method includes providing a pattern of struts interconnected to
form a structure 10 that contacts the walls of a body lumen to
maintain the patency of the vessel. A polymeric sleeve 26,
fabricated as a prepatterned tube, is attached to at least a
portion of an outside surface area 38 of the stent structure.
Fabrication of the polymeric sleeve may be accomplished through
using a variety of different techniques known in the art which
include extrusion, laser cutting, plasma polymerization, slip
casting, injection molding and similar techniques. The pattern of
the polymeric tube may assume any desirable pattern which works to
achieve an appropriate local drug-elution profile.
In an alternative embodiment, the local drug-eluting component 34
includes a plurality of individual filament strands which are
longitudinally positioned across an outside surface 38 of a stent
structure 10 in a spaced apart orientation and attached thereto.
The plurality of individual filament strands are loaded with at
least one therapeutic drug 42 for the release thereof at a
treatment site.
The drug-loaded, polymeric sleeve 26 or the drug-loaded individual
microfilament strands 34 can be processed directly by methods known
in the art, such as by extrusion or plasma polymerization. The
drug-loaded, prepatterned polymeric sleeve or the individual
drug-loaded filament strands are preferably attached to the stent
structure in the final stages of fabricating the drug-eluting stent
delivery system, after the stent is crimped and securely attached
to the balloon using current technology. The polymeric sleeves or
filament strands of appropriate length are attached to the outer
surface of the stent on the delivery system using various
metal-polymer and polymer--polymer bonding technologies, such as
adhesives.
The aforedescribed illustrative stent 10 of the present invention
and similar stent structures can be made in many ways. One method
of making the stent rings 11 is to cut a thin-walled tubular
member, such as stainless steel tubing to remove portions of the
tubing in the desired pattern for the stent, leaving relatively
untouched the portions of the metallic tubing which are to form the
rings. In accordance with the invention, it is preferred to cut the
tubing in the desired pattern using a machine-controlled laser
which process is well known in the art.
After laser cutting, the stent rings are preferably
electrochemically polished in an acidic aqueous solution such as a
solution of ELECTRO-GLO #300, sold by the ELECTRO-GLO Co., Inc. in
Chicago, Ill., which is a mixture of sulfuric acid, carboxylic
acids, phosphates, corrosion inhibitors and a biodegradable surface
active agent. The bath temperature is maintained at about 110
135.degree. F. and the current density is about 0.4 to about 1.5
amps per square inch. Cathode to anode area should be at least
about two to one.
The foregoing laser cutting process to form the cylindrical rings
11 can be used with metals other than stainless steel including
cobalt-chromium, titanium, tantalum, platinum, nickel-titanium, and
alloys thereof, and other biocompatible metals suitable for use in
humans, and typically used for intravascular stents. Further, while
the formation of the cylindrical rings is described in detail,
other processes of forming the rings are possible and are known in
the art, such as by using chemical etching, electronic discharge
machining, stamping, and other processes.
While the invention has been illustrated and described herein, in
terms of its use as an intravascular stent, it will be apparent to
those skilled in the art that the stent can be used in other body
lumens. Further, particular sizes and dimensions, materials used,
and the like have been described herein and are provided as
examples only. Likewise, the invention is not limited to any
particular method of forming the underlying medical device
structure. Other modifications and improvements may be made without
departing from the scope of the invention. Accordingly, it is not
intended that the invention be limited, except as by the appended
claims.
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